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Primary Cilia mediate diverse kinase inhibitor resistance mechanisms in cancer
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1-s2.0-S2211124718307496-main.pdf | Published version | 4.24 MB | Adobe PDF | View/Open |
Title: | Primary Cilia mediate diverse kinase inhibitor resistance mechanisms in cancer |
Authors: | Jenks, AD Vyse, S Wong, JP Kostaras, E Keller, D Burgoyne, T Shoemark, A Tsalikis, A De la Roche, M Michaelis, M Cinatl, J Huang, PH Tanos, BE |
Item Type: | Journal Article |
Abstract: | Primary cilia are microtubule-based organelles that detect mechanical and chemical stimuli. Although cilia house a number of oncogenic molecules (including Smoothened, KRAS, EGFR, and PDGFR), their precise role in cancer remains unclear. We have interrogated the role of cilia in acquired and de novo resistance to a variety of kinase inhibitors, and found that, in several examples, resistant cells are distinctly characterized by an increase in the number and/or length of cilia with altered structural features. Changes in ciliation seem to be linked to differences in the molecular composition of cilia and result in enhanced Hedgehog pathway activation. Notably, manipulating cilia length via Kif7 knockdown is sufficient to confer drug resistance in drug-sensitive cells. Conversely, targeting of cilia length or integrity through genetic and pharmacological approaches overcomes kinase inhibitor resistance. Our work establishes a role for ciliogenesis and cilia length in promoting cancer drug resistance and has significant translational implications. |
Issue Date: | 5-Jun-2018 |
Date of Acceptance: | 3-May-2018 |
URI: | http://hdl.handle.net/10044/1/60292 |
DOI: | https://dx.doi.org/10.1016/j.celrep.2018.05.016 |
ISSN: | 2211-1247 |
Publisher: | Elsevier |
Start Page: | 3042 |
End Page: | 3055 |
Journal / Book Title: | Cell Reports |
Volume: | 23 |
Issue: | 10 |
Copyright Statement: | © 2018 The Authors. his is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/) |
Keywords: | FGFR Hedgehog pathway cilia kinase inhibitor resistance |
Publication Status: | Published |
Conference Place: | United States |
Online Publication Date: | 2018-06-08 |
Appears in Collections: | National Heart and Lung Institute |